In humans, gluten-sensitive enteropathy (GSE) is typically found in individuals genetically predisposed to celiac disease (CD), and in rhesus monkeys as well as in humans it can be induced by a gluten-containing diet. We recently performed experiments where gluten-sensitive and control macaques were fed gluten- containing diets followed by gluten-free diets. Complete recovery was achieved in GSE macaques - based on withdrawal of gluten from their diet. Furthermore, we identified 2 DRB haplotypes and/or 4 DQ allelic pairs as candidate MHC II genes for immunogenetic association with gluten sensitivity in rhesus macaques. Although several useful models have been established to study CD, including transgenic mice expressing HLA-DQ2 allele, there is no satisfactory animal model that would fulfill both genetic and pathologic criteria of this autoimmune disease. We have partially characterized a rhesus GSE model. We believe that such a model will be extremely useful for studies of the immunopathogenesis and treatment of CD. To develop this model further, we plan to: Aim 1: Evaluate an association between clinical, histopathological and immunological surrogates of GSE in rhesus macaques. An association between clinical symptoms (diarrhea, weight loss, skin lesions, etc.), presence of AGA, anti-transglutaminase 2 (TG2) antibodies, villous atrophy, increased presence of IELs and inflammatory-cytokine producing intestinal T lymphocytes in macaques with clinical or subclinical GSE vs. controls will be evaluated. Aim 2: Confirm MHC II alleles that were identified in rhesus macaques as candidates for immunogenetic association with gluten sensitivity. DNA extracted from at least 100 gluten-sensitive and 100 control macaques of Indian origin will be examined for the association with 2 DRB haplotypes and/or 4 DQ allelic pairs that we recently identified as MHC II candidate alleles. We predict that analogous to celiac patients DQ2/8 association will also be confirmed in rhesus macaques with GSE. Aim 3: Evaluate the differences in a2-gliadin digestion between gluten sensitive and control macaques. In pilot study with gluten sensitive and control macaques, it was found that GSE animals but not controls, nor remitted animals, absorb undigested 33-mer across intestinal epithelium. Thus, it was proposed that systemic humoral immune response to dietary gluten is caused by absorption of undigested a2-gliadin across leaky epithelium in GSE macaques with proper MHC II type. Aim 4: Evaluate the oral enzyme treatments in rhesus macaques with GSE. MHC II-pre- selected macaques with gluten sensitivity will be first placed on a gluten-free diet to accomplish remission. In a follow-up gluten challenge, gluten sensitive macaques will be dosed with increasing levels of gluten and a fixed daily oral dose of prolyl endopeptidase from Sphingomonas capsulata, cysteine endoprotease EP-B2 from barley, and the two-enzymes together to evaluate their therapeutic potential.